Living bone tissue exhibits a dynamic equilibrium between deposition and resorption of bone. These processes are mediated primarily by two cell types: osteoblasts, which secrete molecules that comprise the organic matrix of bone, and osteoclasts, which mediate the dissolution of the bone matrix and solubilization of bone salts. In young individuals with growing bone, the rate of bone deposition exceeds the rate of bone resorption, while in older individuals the rate of resorption may exceed deposition leading to net loss of bone mass. The latter situation can lead to increased risk of bone fracture and slow or incomplete repair of broken bones. Understanding the molecular mechanisms that underlie these processes is critical to the development of therapeutics for the treatment of bone diseases. Human genetics has played a major role in the elucidation of these mechanisms and has enabled the identification of multiple factors involved in both catabolic and anabolic bone activity (Janssens and Van Hul, Hum Mol Gen, 11(20):2385-93, 2002; Ralston, J Clin Endocrin Metab. 87(6):2460-66, 2002).
Dickkopf-1 (Dkk-1) is a member of the dickkopf family of proteins that have been shown to be negative regulators of the canonical Wnt-signaling pathway, which has a central role in bone development and formation (see, for example, Glinka et al., Nature 391:357-62 (1998); Fedi et al., J Biol Chem 274(27):19465-72 (1999); Zorn, Curr Biol 11:R592-95 (2001); and Krupnik et al., Gene 238: 301-13 (1999)). Dkk-1 inhibits Wnt signaling through its interaction with the Wnt co-receptors LRP5 or LRP6 and the kremen proteins (see, for example, Bafico et al., Nature Cell Biol 3:683 (2001); Mao et al., Nature 411(17):321 (2001); Mao et al., Nature 417:664 (2002); and Semënov et al., Curr Biol 11:951-61 (2001). By binding LRP5 (LRP6) and kremen proteins, Dkk-1 prevents LRP5 or LRP6 from associating with members of the Wnt pathway and thus prevents Wnt-mediated signal transduction, which in turn results in the inhibition of bone formation.
LRP5 is a key protein in regulating bone mass (see, for example, Gong et al., Cell 107:513-23 (2001); Patel, N Eng J Med 346(20):1572 (2002)). An autosomal recessive disorder characterized by low bone mass (osteoporosis-pseudoglioma syndrome, or “OPPG”) has been identified as being caused by loss-of-function mutations in LRP5 (Gong et al., 2001). In addition, gain-of-function mutations in LRP5 have been shown to result in autosomal dominant high bone mass in humans (Little et al., Am J Human Genetics. 70(1):11-19, 2002). The same mutations in LRP5 that result in high bone mass can interfere with the ability of Dkk-1 to inhibit LRP5 signaling (see, for example, Boyden et al., N Eng J Med. 346(20):1513-1521, 2002). Thus, Dkk-1 is appropriately characterized as being a negative regulator of bone deposition.
In view of the involvement of Dkk-1 in the regulation of bone formation and its role in various other diseases that are associated with bone loss (e.g., cancer and diabetes), there is a need for improved anti-Dkk-1 antibodies for therapeutic use and for other purposes.